CN101094667A - Hypocholesterolemic compositions comprising a statin and an antiflatulent agent - Google Patents

Hypocholesterolemic compositions comprising a statin and an antiflatulent agent Download PDF

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Publication number
CN101094667A
CN101094667A CNA2005800056595A CN200580005659A CN101094667A CN 101094667 A CN101094667 A CN 101094667A CN A2005800056595 A CNA2005800056595 A CN A2005800056595A CN 200580005659 A CN200580005659 A CN 200580005659A CN 101094667 A CN101094667 A CN 101094667A
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pharmaceutical composition
statins
agent
simethicone
antiflatulent
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M·格雷罗
A·奥里奥尔斯
M·M·拉加
A·古列塔
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Ferrer Internacional SA
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Ferrer Internacional SA
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Abstract

The present invention relates to hypocholesterolemic compositions comprising statins plus antiflatulent agents. In particular the compositions of the present invention comprise a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, whether in free form or as pharmaceutically acceptable salts and hydrates thereof, plus an antiflatulent agent. selected from the group consisting of simethicone and dimethicone. The combination of statins plus antiflatulent agents is useful in the prevention and management of flatulence caused by statins.

Description

The hypocholesterolemic compositions that comprises statins and antiflatulent agent
Invention field
The present invention relates to comprise cholesterol reducing (hypocholesterolemic) compositions of statins and antiflatulent agent.
Background of invention
Statins is the inhibitor of Hydroxymethylglutaryl-CoA reductase, and this enzyme is the synthetic a kind of key enzyme of cholesterol, and it is the concentration of cholesterol reducing directly.Known these chemical compounds are safety and effective cholesterol-lowering agent, so they are to treatment coronary heart disease and the important therapeutical effect that shown that reduces by the serious caused M ﹠ M of cardiovascular pathology disease of this class.
Normally used statins is atorvastatin (USP 5273995) in medical science, cerivastatin (USP 5177080), fluvastatin (USP 4739073), lovastatin (USP4231938), pravastatin (USP 4346227), rosuvastatin (USP RE 37314) and simvastatin (USP 4444784).Can use their free form or its pharmaceutically acceptable salt, be generally alkali metal or alkali salt, it is anhydrous or hydration; Usually it is desirable to use its sodium salt or calcium salt.For example, in clinical practice, employed atorvastatin is (2: 1) trihydrate forms of sodium salt, and cerivastatin, fluvastatin and pravastatin are sodium-salt form, and rosuvastatin is a sodium-salt form, and lovastatin and simvastatin are free form.A kind of chemical compound of renewal, Pitavastatin (pitavastatin) (EP 304063) is in the III phase to study at present in Europe.
WO 03/074034 has described and has contained the anti-hypercholesterolemicdrugs drugs that postpone to discharge such as the pharmaceutical composition of statins.The stable tablet that comprises simvastatin has been described in WO03/086387.
Remarkable and the most common side effect of statins be flatulence (149 (1), 123-9[PubMed 10704623 for Bakker-Arkema etc., Atherosclerosis 2000 Mar]; Black etc., Arch Intern Med 1998 Mar 23,158 (6), 577-84[PubMed9521221]; Posvar etc., J Clin Pharmacol 1996 Aug, 36 (8), 728-3 1[PubMed 8877677]; Boccuzzi etc., Am J Cardiol 1991 Nov 1,68 (11), 1127-31[Pubmed 1951069]; Zeller etc., Drug Intell ClinPharm 1988 Jul-Aug, 22 (7-8), 542-5[PubMed 3046888]), because its symptom is similar with those symptoms for the coronary heart disease of the target of carrying out blood fat reducing treatment with statins, flatulence is to cause the reason that does not accommodate the symptom confusion.
Can reduce one of flatulent material is the antiflatulent agent with froth breaking effect.For example, Simethicone and simethicone successfully are applied to treat flatulence and meteorism.If further use suitable health care/dietary means, for example, it is effective avoiding drinking soda pop and making flatulent food, these chemical compounds.For example, in WO 95/01780, described and comprised H 2Antagonist is famotidine for example, the pharmaceutical composition of the alginate and the Simethicone of the anti-flatulent amount of choosing wantonly.
Described the compositions that is used to form the compression solid dosage form in EP-A 1297825, it is a Simethicone, the free-pouring mixture of adsorbent and the activating agent of choosing wantonly.
The commodity that some comprised statins, as Lipitor (Atorvastatin calcium, 2: 1 trihydrate) and the preparation (WO 2004/021972) that comprises statins for example pravastatin (WO 03/057195) and defoamer, prepare together as the Simethicone emulsion.Yet the ratio of this chemical compound is very low, and only is used as pharmaceutical carrier.
Goal of the invention
The purpose of this invention is to provide and comprise statins and be the hypocholesterolemic compositions of target to remove by the caused flatulence of statins by the froth breaking effect in the antiflatulent agent of active component ratio.
The combination of statins and antiflatulent agent can be used for preventing and treating the flatulence that is caused by statins.Because coronary heart disease and flatulence are accompanied by the imbalance of breast abdomen, so this makes the patient have better compliance and symptom is had better clinical understanding treatment.
Summary of the invention
The present invention relates to comprise suitable proportion as the statins of active component and the pharmaceutical composition of antiflatulent agent.
Compositions of the present invention preferably comprises and is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, Pitavastatin, pravastatin, the statins of rosuvastatin and simvastatin, it is free form or its pharmaceutically acceptable salt and hydrate and the antiflatulent agent that preferably is selected from Simethicone and simethicone.
Compositions of the present invention can be Orally administered, preferably with solid or forms of liquid compositions for example tablet, especially coated tablet, and capsule, syrup, solution, powder, granule, forms such as emulsion are used.
Preferred tablet, and preferred especially coated tablet.
Statins can exist with the amount of 0.1 to 100mg/ sheet in tablet.And antiflatulent agent can exist with the ratio of 25 to 250mg/ sheets in tablet.
Compositions of the present invention further is included in the normally used diluent that is selected from the pharmaceutical technology, binding agent, other component of the group that disintegrating agent and lubricant and composition thereof are formed.The pharmaceutical excipient that can randomly add other is as antioxidant and wetting agent.
Because statins is a heliosensitivity, the tablet that therefore for example has the coating that comprises cellulose or acrylic acid derivative and plasticizer and opacifier is convenient to protect said composition.Randomly, can add different coloring agent.
The accompanying drawing summary
Fig. 1 represents that embodiment 4 comprises simvastatin and Simethicone, and the external stripping curve represented with meansigma methods of other identical tablet that does not contain Simethicone.
Detailed Description Of The Invention
The present invention relates to comprise the anti-inflatable as active component of statins and suitable proportion The pharmaceutical composition of agent.
The antiflatulent agent as active component of suitable proportion refers to the anti-Flatulence of described medicament Amount, the amount that namely provides anti--Flatulence effectively to alleviate. Similarly, medicine group of the present invention Compound comprises at least a statins, and the amount of statins can provide effective after using The ground Lowering cholesterol effect.
According to an aspect of the present invention, the effective dose of antiflatulent agent depends on statins Amount. Therefore, according to an embodiment, antiflatulent agent is with respect to the weight ratio of statins Be at least 0.25, preferably be at least 0.50,0.75 or 1.00, particularly be at least 1.25 Or 1.50. Described ratio refers to the relative quantity used or with statins and anti-inflatable The relative quantity that exists is prepared-is referred in agent jointly in preparation. Antiflatulent agent is with respect to statins Maximum ratio be not particularly limited. Yet the amount of antiflatulent agent is no more than the total formulation weight amount A certain ratio is favourable. High 50% weight to preparation, especially high ratio to 30% weight Favourable.
Composition of the present invention comprises and preferably is selected from Atorvastatin, cerivastatin, and fluorine cuts down His spit of fland, Lovastatin, Pitavastatin, Pravastatin, he of rosuvastatin and Simvastatin Spit of fland class medicine, it is free form or its pharmaceutically acceptable salt and hydrate and preferably Be selected from the antiflatulent agent of Simethicone and dimeticone.
Preferably, use the trihydrate of Atorvastatin calcium (2: 1), cerivastatin, fluorine cuts down The sodium salt of his spit of fland and Pravastatin, the calcium salt of rosuvastatin and the Lovastatin of free form and Simvastatin.
Composition of the present invention can be Orally administered, preferably with the form of solid composite for example Tablet, especially coated tablet, capsule, powder, particle etc., or with the shape of fluid composition Formula is syrup for example, solution, and the forms such as emulsion are used. Solid composite, especially tablet, the spy Not that coated tablet is preferred. The statins that more than provides and the relative quantity of antiflatulent agent Ratio is applicable to any one in these preparation types.
Statins can the amount with 0.1 to 100mg/ sheet exist in tablet. Therefore, exist Standard film heavily is in the situation of 400mg, the proportion of statins can for 0.025 to 25%. Common, the amount of every statins can be 0.1,2.5,5,10,20, 40 and 80mg. Therefore, for the standard tablet of 400mg, the ratio of statins can be divided Be not 0.025%, 0.625%, 1.25%, 2.5%, 5%, 10% and 20%. Similarly ratio is suitable Be used for other composition.
And antiflatulent agent can the amount with 25 to 250mg/ sheets exist in tablet. Therefore, right In the standard tablet for 400mg, the proportion of antiflatulent agent can be 6.25 to 62.5%. Similarly ratio is applicable to other composition, and correspondingly it contains composition weight at least 6.25%, preferred more than 10%, the antiflatulent agent more than 20% especially.
Coated tablet comprises label and dressing. In this case, preferred label comprises statins Thing and antiflatulent agent.
Preferred diluent is microcrystalline cellulose and derivative thereof, for example Prosolv in tablet of the present invention, it is the mixture of microcrystalline cellulose and cataloid, lactose, and sweet mellow wine, Calcium phosphate, starch etc. Preferably, microcrystalline cellulose is AvicelPH102 and Prosolv。
Preferred adhesive is a starch in tablet of the present invention, Polyethylene Glycol, polyvinylpyrrolidone, cellulose derivative, for example hypromellose etc.
Preferred disintegrating agent is a silica sol in tablet of the present invention, croscarmellose, polyvinylpyrrolidone, starch, and pregelatinated derivant, for example Primojel , it is a sodium starch glycollate, etc.Preferably, use Aerosil , Acdisol And polyvinylpyrrolidone.
Preferred lubricant is a Pulvis Talci in tablet of the present invention, magnesium stearate, and stearic acid, sodium stearyl fumarate, high-molecular weight Polyethylene Glycol (4000-8000), as PEG 8000, or the like.Preferably, use sodium stearyl fumarate, Pulvis Talci and magnesium stearate.
Other drug excipient resembles antioxidant such as butylated hydroxyanisol, ascorbic acid or gluconic acid lactone, etc. and wetting agent such as sodium lauryl sulphate, etc., can randomly add.
Tablet of the present invention preferably has the coating of lucifuge.Preferably, this coating is by cellulose derivative, for example, hypromellose (HPMC) sodium, acrylic polymer, plasticizer, citric acid diethylester for example, opacifier, titanium dioxide for example, Pulvis Talci and stearic acid are formed.They can randomly comprise and be used for the painted pigment of tablet.As pigment, preferred ferric oxide derivatives.
The method that is used to prepare statins and antiflatulent agent label can be precompressed, and promptly this mixture of compacting in advance sieves and final tabletting then.They can also obtain by using pure aqueous solvent wet granulation.These are the conventional methods in the drug technique.
Yet the applicant finds that tablet of the present invention advantageously can pass through straight pressing, promptly by all components are directly prepared.Therefore, with the Simethicone of liquid to be adsorbed for example Prosolv of agent , mannitol, the form of the adsorbate of anhydrous colloidal silica (silicon dioxide) or lactose is mixed.Sieve then, mix obtaining final mixture with other component.Preferred straight pressing rather than common preloading method are because its cost is lower, and are easier to large-scale production.
The existence of antiflatulent agent can not influence the dissolubility of tablet of the present invention.Therefore, Fig. 1 shows that embodiment 4 comprises antiflatulent agent, and promptly the stripping curve of the new tablets of Simethicone does not have difference with the conventional tablet that does not contain antiflatulent agent.Thereby, the pharmacy behavior and the there was no significant difference of two kinds of preparations, the patient takes the treatment that statins carries out and can easily be replaced by tablet of the present invention like this.
To further explain the present invention by following examples, but the present invention is not limited to following examples.
Embodiment 1: the 400mg tablet that comprises 40mg atorvastatin (calcium trihydrate) and 115mg Simethicone
Atorvastatin (calcium trihydrate) 40mg
Simethicone 115mg
Colloidal silica anhydrous 10mg
Cross-linked carboxymethyl cellulose sodium 10mg
Sodium stearyl fumarate 15mg
Microcrystalline Cellulose Avicel PH102 is in right amount to 400mg
Embodiment 2: the 400mg tablet that comprises 20mg simvastatin and 125mg Simethicone
Simvastatin 20mg
Simethicone 125mg
Polyvinylpyrrolidone 15mg
Cross-linked carboxymethyl cellulose sodium 5mg
Sodium stearyl fumarate 15mg
Sodium lauryl sulphate 4mg
Butylatedhydroxyanisole 5mg
Lactose is in right amount to 400mg
Embodiment 3: the 400mg tablet that comprises 10mg pravastatin sodium and 125mg Simethicone
Pravastatin sodium 10mg
Simethicone 125mg
Primojel 20mg
Pulvis Talci 12mg
Magnesium stearate 4mg
Prosolv In right amount to 400mg
Embodiment 4: the 400mg tablet that comprises 40mg simvastatin and 125mg Simethicone
Simvastatin 40mg
Simethicone 125mg
Primojel 16mg
Silicon dioxide 43mg
Pulvis Talci 12mg
Magnesium stearate 4mg
Lactose (directly compacting) is in right amount to 400mg

Claims (24)

1, pharmaceutical composition comprises the statins and the antiflatulent agent as active component of suitable proportion.
2, according to the pharmaceutical composition of claim 1, wherein said statins is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, Pitavastatin, pravastatin, rosuvastatin and simvastatin, and pharmaceutically acceptable salt and hydrate.
3, according to the pharmaceutical composition of claim 2, wherein said statins is a simvastatin, or its pharmaceutically acceptable salt.
4, according to each pharmaceutical composition of claim 1 to 3, wherein said antiflatulent agent is selected from Simethicone and simethicone.
5, according to the pharmaceutical composition of claim 4, wherein said antiflatulent agent is a Simethicone.
6, according to each pharmaceutical composition of aforementioned claim, wherein said compositions is tablet, capsule, syrup, solution, powder, granule or emulsion.
7, according to the pharmaceutical composition of claim 6, wherein said tablet is a coated tablet.
8, according to the pharmaceutical composition of claim 7, wherein said coated tablet comprises label and coating, and described label comprises described statins and described antiflatulent agent.
9, according to each pharmaceutical composition of aforementioned claim, wherein antiflatulent agent is at least 0.25 with respect to the weight ratio of statins.
10, according to each pharmaceutical composition of aforementioned claim, wherein antiflatulent agent is at least 1.50 with respect to the weight ratio of statins.
11, according to the pharmaceutical composition of claim 6 or 7, wherein simvastatin exists with every 2.5 to 100mg amount.
12, according to the pharmaceutical composition of claim 11, wherein simvastatin exists with every 5 to 80mg amount.
13, according to the pharmaceutical composition of claim 6 or 7, wherein Simethicone exists with every 25 to 250mg amount.
14, according to the pharmaceutical composition of claim 13, wherein Simethicone exists with the amount of every 125mg.
15, according to each pharmaceutical composition of aforementioned claim, further comprise one or more diluent, one or more binding agents, one or more disintegrating agents and one or more lubricants.
16, according to the pharmaceutical composition of claim 15, wherein said diluent is selected from microcrystalline Cellulose and derivant thereof, lactose, mannitol, calcium phosphate, starch and composition thereof.
17, according to the pharmaceutical composition of claim 15, wherein said binding agent is selected from starch, Polyethylene Glycol, polyvinylpyrrolidone, cellulose derivative and composition thereof.
18, according to the pharmaceutical composition of claim 15, wherein said disintegrating agent is selected from silica sol, croscarmellose, polyvinylpyrrolidone, starch and pregelatinated derivant thereof and composition thereof.
19, according to the pharmaceutical composition of claim 15, wherein said lubricant is selected from Pulvis Talci, magnesium stearate, stearic acid, sodium stearyl fumarate, PEG 8000 and composition thereof.
20, according to each pharmaceutical composition of aforementioned claim, further comprise one or more antioxidants, and one or more wetting agent.
21, according to the pharmaceutical composition of claim 7, the coating of wherein said tablet comprises cellulose derivative or its pharmaceutically acceptable salt, acrylic polymer, triethyl citrate, titanium dioxide, and one or more lubricants.
22, according to the pharmaceutical composition of claim 21, wherein said cellulose derivative is a hydroxypropyl emthylcellulose.
23, according to each pharmaceutical composition of aforementioned claim, further comprise one or more coloring agent.
24, prepare according to each the method for pharmaceutical composition of aforementioned claim by its component of direct compacting.
CNA2005800056595A 2004-02-03 2005-02-02 Hypocholesterolemic compositions comprising a statin and an antiflatulent agent Pending CN101094667A (en)

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EP04002317A EP1563837A1 (en) 2004-02-03 2004-02-03 Hypocholesterolemic compositions comprising a statin and an antiflatulent agent

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AU (1) AU2005210117A1 (en)
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DK2018153T3 (en) 2006-04-26 2012-07-23 Rosemont Pharmaceuticals Ltd Liquid oral compositions
WO2007131517A1 (en) * 2006-05-12 2007-11-22 Pharmathen S.A. Pharmaceutical formulation containing an hmg-coa reductase inhibitor and method for the preparation thereof
CN101229187B (en) * 2007-01-23 2011-09-28 德国柏林化学股份有限公司 Simethicone emulsion and preparing method thereof
CN104244946A (en) * 2012-04-30 2014-12-24 霍夫曼-拉罗奇有限公司 New formulation

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EP1713469A1 (en) 2006-10-25
JP2007520514A (en) 2007-07-26
WO2005074915A1 (en) 2005-08-18
AU2005210117A1 (en) 2005-08-18
UY28729A1 (en) 2005-03-31
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CA2556181A1 (en) 2005-08-18
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